Glaucoma is a leading cause of blindness. Elevated intraocular pressure (IOP) is a major risk factor for glaucoma. Our goal is to continue to identify and characterize genetic factors that contribute to elevated IOP and glaucoma. We are using the mouse as a model system to conduct a phenotype driven mutagenesis screen to identify novel mechanisms and pathways involved in glaucoma pathogenesis. The power of a phenotype driven screen is that there is no requisite, a priori information for factors or pathways involved. In our previous funding period, we have identified a number of glaucoma relevant mouse mutants (Grms) that show hallmarks of glaucoma including high IOP, retinal ganglion cell death and optic nerve atrophy. In this proposal, we will identify the causative mutations in a few of these glaucoma-relevant mutants that we have started to study. We will characterize the genetic pathways involved and carry out more detailed investigations into the pathogenesis. Very few mouse models of glaucoma exist and our mutants will be valuable both as models for understanding human glaucoma and for facilitating the identification of human mutations. Since the small number of available mutants severely limits mouse studies of glaucoma, we propose a new Cyp 1b1 -sensitized END screen for dominant glaucoma mutations. A number of reported human glaucoma loci have a dominant effect. Mutations in the human CYP1B1 gene predispose people to high IOP and glaucoma, a predisposition we have repeated in mice. We will screen 1000 G1 males/year for IOP elevation and other ocular abnormalities, ten times more families than was possible in the previous granting period. We anticipate producing 15-40 glaucoma- relevant mutants that will be made available to the glaucoma community as quickly as is feasible. We are confident that continuing to use the power of a phenotype-driven mutagenesis screen in parallel with our unique tools to examine ocular phenotypes will enable us to identify and characterize new genetic factors that contribute to elevated IOP and glaucoma. The new mutants have great potential to transform our understanding of glaucoma. Relevance to Public Health: Glaucoma is one of the leading causes of blindness. Over 20 regions of the human genome have been implicated in glaucoma but very few genes have been identified. Our proposal aims to produce mouse models of human glaucoma to be used as tools to understand the mechanisms of glaucoma, to help identify human glaucoma genes and to test new treatments.